xevinapant (Debio 1143) / Debiopharm, Ascenta, Ascentage Pharma, EMD Serono - LARVOL DELTA

The smac mimetic Xevinapant increases the efficacy of radiotherapy in triple negative breast cancer but only in the presence of tumor necrosis factor alpha (AACR 2026) - "Xevinapant (AT406) synergizes with RT in the presence of TNFα to induce the death of triple-negative breast cancer cells. TNFα is central to this radiosensitization through activation of the programmed cell death. These results are promising, and investigations are underway to characterize a potential TNFα gene signature that could be used to identify patients that could respond to such a combination therapy."

Clinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CASP3 • CASP7 • ER • HER-2 • TNFA

SOX9-ICASPASE9 MOUSE MODEL WOULD BE ABLE TO GENERATE CHIMERIC KIDNEY (ISN-WCN 2026) - "Adding AP20187 (100 nM) and AT406 (50 μM) made those Sox9-positive cells eliminate...When donor's UPCs connect to recipient's UPCs and ureter, urine produced by donor kidney cells can excreted via the recipient's ureter. We are trying to make chimeric kidneys with this system."

Preclinical • Infectious Disease • HOXB7 • SOX9

Absolute Bioavailability and Absorption, Distribution, Metabolism, and Excretion of [14C]Xevinapant, a Potent, Oral, Small-Molecule IAP Inhibitor. (PubMed, Clin Pharmacol Drug Dev) - "The absolute oral bioavailability of xevinapant was determined to be 57.8%. The clearance of [14C]xevinapant was 12.2 L/h and the volume of distribution at steady-state was 75.3 L. Xevinapant was well tolerated in healthy male subjects, with no clinically significant findings in clinical laboratory evaluations, vital signs, ECG, or physical examinations."

Journal

Xevinapant or Placebo Plus Platinum-Based Chemoradiotherapy in Unresected Locally Advanced Squamous Cell Carcinoma of the Head and Neck (TrilynX): A Randomized, Phase III Study. (PubMed, J Clin Oncol) - "Xevinapant plus CRT did not improve EFS (EFS was shorter with xevinapant v placebo) and demonstrated an unfavorable safety profile versus placebo plus CRT in patients with unresected LA SCCHN."

Clinical • Journal • P3 data • Head and Neck Cancer • Hematological Disorders • Neutropenia • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Comparing and combining xevinapant with ATR and PARP inhibition for the radiosensitization of HPV-negative HNSCC cells. (PubMed, Sci Rep) - "Both tuvusertib and olaparib induced stronger radiosensitization than xevinapant and combining both agents resulted in especially profound radiosensitization in three out of the four cell lines tested, whereas their combination with xevinapant or the combination of xevinapant with cisplatin was less effective. Assessment of cell death induction via annexin V/DAPI staining failed to generally predict cytotoxicity or radiosensitization of these approaches. Overall, our data are in line with the recent failure of the phase 3 TrilynX trial and suggest further investigation of ATR and PARP inhibition for the curative treatment of HPV-negative HNSCC."

Clinical • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ANXA5

Adjuvant Palbociclib for ER+ Breast Cancer in the PALLAS Trial (ABCSG-42/AFT-05/PrE0109/BIG-14-13): Post-Recurrence Treatment and Overall Survival (SABCS 2025) - " 5,796 pts enrolled at 406 centers in 21 countries worldwide over 3 y. In the intent-to-treat (ITT) population, with a median follow-up of 82.7 months (mo), 7-y outcomes for iDFS, DRFS and OS are shown in the table. The PALLAS trial revealed significant differences in treatment post-DR that impact OS. Reduced/delayed use of metastatic CDK4/6i after adjuvant P was associated with significantly poorer OS, suggesting that patients who relapse after adjuvant CDK4/6i may still benefit from metastatic CDK4/6i. This has implications for optimal treatment in those who relapse after adjuvant CDK4/6i and warrants further study to determine if this is therapy-specific or an overarching biological effect."

Clinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • HER-2

Identification, structural elucidation and nonclinical characterization of oxMET1: A further major metabolite of xevinapant? (PubMed, Xenobiotica) - "Based on these findings, this metabolite did not raise safety concerns according to the MIST guidelines, however it warrants further characterization of its drug-drug interaction (DDI) potential according to current DDI guidelines. The integrated workflow presented here highlights the importance of metabolite characterization in drug development."

Journal • Oncology

IAP Antagonists Selectively Eliminate Therapy-Induced Senescent Cancer Cells via TNFα-Independent Apoptosis. (PubMed, Cancer Sci) - "Here, we show that AZD5582 and AT406, potent antagonists of cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1 and cIAP2) and X-linked inhibitor of apoptosis protein (XIAP), selectively eliminated HCT116 and RKO cells that had undergone senescence following treatment with a chemotherapeutic agent such as trifluridine, camptothecin, or doxorubicin. At physiological concentrations, TNFα sensitized non-senescent, proliferating cancer cells, but not TIS and nutlin-3a-induced senescent cancer cells, to apoptosis in the presence of IAP antagonists. Collectively, these findings suggest that IAP antagonists could serve as effective concomitant agents to TIS-inducing chemotherapy that promotes TNFα secretion within tumors, functioning not only as TNFα-independent senolytics but also as potentiators of TNFα-mediated apoptosis in adjacent non-senescent, proliferating cancer cells."

Journal • Oncology • BIRC3 • CASP8 • TNFA • XIAP

Ex Vivo Drug Efficacy in High-Risk Paediatric Cancers: A Comprehensive Analysis of the ZERO Cohort (LCC 2026) - "Notably, brain tumour samples demonstrated differential sensitivity to Mitogen-Activated Protein Kinase signalling pathway (MAPK) inhibitors with strong correlations observed with the JAK/STAT pathway inhibitor ruxolitinib and with xevinapant, a SMAC mimetic that targets anti-apoptotic signalling proteins (XIAP, cIAP1/2). Conclusion Our HTS pipeline revealed tumour-type specific sensitivities and novel drug-drug correlations, which may guide future combination efficacy testing and serve as predictive markers for potential drug responses. Further evaluation of the improved ZERO program will uncover additional drug correlations, paving the way for innovative therapies in paediatric cancer"

Preclinical • Brain Cancer • Neuroblastoma • Oncology • Pediatrics • Sarcoma • Solid Tumor • XIAP

SMAC Mimetic Targets Glioblastoma Stem Cells and Reprograms the Associated Tumor Microenvironment (SNO 2025) - "Taken together, our findings highlight the dual mechanism of action of Xevinapant in targeting both tumor-intrinsic and microenvironmental resistance mechanisms. These results support the continued clinical development of Xevinapant and provide a strong rationale for combination strategies aimed at improving treatment efficacy in GBM."

Biomarker • Tumor microenvironment • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

SMAC Mimetic Targets Glioblastoma Stem Cells and Reprograms the Associated Tumor Microenvironment (WFNOS 2025) - P | "Taken together, our findings highlight the dual mechanism of action of Xevinapant in targeting both tumor-intrinsic and microenvironmental resistance mechanisms. These results support the continued clinical development of Xevinapant and provide a strong rationale for combination strategies aimed at improving treatment efficacy in GBM."

Biomarker • Tumor microenvironment • Brain Cancer • Glioblastoma • Solid Tumor

Sox9-iCaspase9 Mouse Model for Inducible Ureteric Bud Ablation to Generate Chimeric Scaffolds for Kidney Regeneration (KIDNEY WEEK 2025) - "AP20187 and AT406 were daily added to the culture medium to eliminate Sox9-positive cells...This approach could be crucial for overcoming species-specific barriers in the generation of kidney chimeras. This Sox9-iC9 mouse model is a promising platform for these critical next steps."

Preclinical • SOX9

In vitro-in vivo extrapolation of intrinsic clearance based on data from human hepatocyte spheroids - A case study with the low-clearance drug xevinapant. (PubMed, Xenobiotica) - "The remaining clearance is renal (∼20%) and metabolic, but potentially extrahepatic (∼50%).4. This research highlights the importance and benefits of utilizing advanced in vitro techniques, such as human hepatocyte spheroids, to accurately characterize drug metabolism, providing valuable insights for pharmacokinetic evaluations and, ultimately, supporting the development of a PBPK model and understanding the DDI risk of xevinapant."

Journal • Preclinical • Head and Neck Cancer • Oncology • Solid Tumor

Green and sustainable synthesis of antimicrobial silver nanoparticles from cold-pressed bitter almond oil residue. (PubMed, Bioorg Chem) - "Phytochemical analysis showed REE was rich in chlorogenic acid (45.19 %) and quercetin (31.73 %), while RSS contained a higher quercetin concentration (88.34 %). Nanoparticle formation was confirmed by UV-Vis spectroscopy, showing surface plasmon resonance at 406.5 nm (REE-AgNPs) and 410 nm (RSS-AgNPs)...These results highlight bitter almond residues as valuable, eco-friendly resources for green nanoparticle synthesis. The study contributes to advancing bioeconomy strategies and developing sustainable nanotechnologies for environmental and biomedical applications."

Journal

Xevinapant plus chemoradiotherapy negatively sculpts the tumour immune microenvironment in head and neck cancer. (PubMed, Cancer Res Commun) - "Furthermore, combination treatment significantly downregulated gene expression associated with immune-related pathways, increased levels of immunodysregulatory acute phase proteins and decreased levels of necroptosis mediator RIPK3. Overall, xevinapant plus CRT has an immunosuppressive effect on the tumour-immune microenvironment which may explain its lack of clinical benefit."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • NR4A3

BONE METABOLIC DISORDERS AS THE FIRST MANIFESTATION OF AUTOIMMUNE ENTEROPATHIES (UEGW 2025) - "Laboratory abnormalities included CRP at 6.78 mg/L, fecal calprotectin >1000 μg/g, total IgA at 1.91 g/L, and Anti-tTG IgA at 406.1 RU/mL...The therapeutic approach was tailored to the patient's condition: biological therapy (Infliximab), a gluten-free diet, bisphosphonates, calcium, and vitamin D supplementation. Both Crohn's and Celiac disease are primarily considered gastrointestinal (GI) disorders, but they are systemic conditions that may present with a broad range of extraintestinal manifestations. Both Crohn's and Celiac disease are primarily considered gastrointestinal (GI) disorders, but they are systemic conditions that may present with a broad range of extraintestinal manifestations. These may develop earlier than, or in the absence of, classic GI symptoms and may be the only indication of the underlying condition. Patients presenting with osteopenia, osteoporosis, or fractures may initially be evaluated for metabolic bone disorders, while..."

Back Pain • Celiac Disease • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammatory Bowel Disease • Lumbar Back Pain • Metabolic Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Osteoporosis • Pruritus • Rheumatology

Anticandidal activity of greenly synthesized silver nanoparticles formulated using Alkanna tinctoria roots against multidrug resistant candidal pathogens. (PubMed, Sci Rep) - "Characterization confirmed spherical At-AgNPs with 19.91 nm diameter by TEM and 120.6 nm hydrodynamic size, exhibiting a UV-Vis peak at 406.27 nm...SEM imaging revealed extensive morphological damage to fungal cells following combination treatment. These results position At-AgNPs as a viable adjunct therapy capable of boosting conventional treatment effectiveness while potentially lowering required drug doses and minimizing side effects in resistant Candida infections."

Journal • Candidiasis • Infectious Disease

Synthesis of the 1,5-Diazabicyclo[6.3.0]dodecane Core Structure of Xevinapant. (PubMed, J Org Chem) - "1,5-Diazabicyclo[6.3.0]dodecanone amino acid scaffold serves as an important scaffold for developing SMAC mimetics, including clinical candidates like Xevinapant and Dasminapant. Herein, we report a novel, efficient, and potentially scalable synthesis of the core structure of Xevinapant achieved in 7 steps from a pyroglutamic acid derivative, with an overall yield of 8.4%, facilitating further development of IAP inhibitors."

Journal • Oncology

Innovative first-order UV and fluorescence spectroscopic methods for the quantification of rufinamide in the presence of its toxic degradant: Application of AGREE tool. (PubMed, Spectrochim Acta A Mol Biomol Spectrosc) - "The RUF's fluorescence and the oxidative degradant (OXD) emission appeared at 406 and 426 nm, following the excitation at 373 and 368 nm respectively. The limit of quantitation (LOQ) values were of 0.14 and 0.27 μg mL-1, while the limit of detection (LOD) values were 8.19 and 0.41 μg mL-1 for spectrophotometric and spectrofluorometric methods respectively. AGREE and analytical eco-scale was two of the tools used to assess and approve the proposed method's greenness."

Journal • CNS Disorders • Epilepsy

The reprogramming impact of SMAC-mimetic on glioblastoma stem cells and the immune tumor microenvironment evolution. (PubMed, J Exp Clin Cancer Res) - "In summary, Xevinapant exhibits robust anti-tumor activity on GSCs and favorable immune modulation of the TME in GBM, hence providing a rationale for further clinical investigation in GBM."

Biomarker • Journal • Brain Cancer • Glioblastoma • Glioma • Immune Modulation • Immunology • Oncology • Solid Tumor

Erythrocytosis as an indicator of disease progression of small cell lung cancer: A case report. (PubMed, Respir Med Case Rep) - "The patient underwent stereotactic radiosurgery (SRS) and received four cycles of combination therapy with cisplatin, etoposide, and durvalumab, followed by maintenance therapy with durvalumab to achieve disease control...Concurrently, new brain metastatic lesions were identified, and serum erythropoietin (EPO) levels were markedly elevated at 406 mIU/mL...Notably, WBRT appeared to contribute to the normalization of serum EPO levels and resolution of polycythemia. This report elucidates the clinical course and relevance of this condition based on a literature review."

Journal • Hematological Disorders • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

XXL_2022-01: Study Comparing RT With Cetuximab + Xevinapant to RT With Cetuximab-placebo in Patients With Head and Neck Cancer (clinicaltrials.gov) - P3 | N=19 | Terminated | Sponsor: Groupe Oncologie Radiotherapie Tete et Cou | Trial completion date: Mar 2025 ➔ Sep 2024 | Completed ➔ Terminated; toxicity

Trial completion date • Trial termination • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

XXL_2022-01: Study Comparing RT With Cetuximab + Xevinapant to RT With Cetuximab-placebo in Patients With Head and Neck Cancer (clinicaltrials.gov) - P3 | N=19 | Completed | Sponsor: Groupe Oncologie Radiotherapie Tete et Cou | Suspended ➔ Completed | Trial completion date: Oct 2035 ➔ Mar 2025 | Trial primary completion date: Oct 2025 ➔ Dec 2024

Trial completion • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Xevinapant plus avelumab in advanced solid tumours, with a dose expansion in advanced non-small-cell lung cancer: exploratory biomarker, safety and efficacy analyses from an open-label, nonrandomised phase Ib study. (PubMed, Ther Adv Med Oncol) - P1 | "NCT03270176 (https://clinicaltrials.gov/study/NCT03270176). Registered on ClinicalTrials.gov on 29 August 2017."

Biomarker • IO biomarker • Journal • P1 data • Fatigue • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • CD8 • IL10 • IL13 • IL1B

Radio-sensitizing activity in apoptosis pathway in HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC) (AACR 2025) - "This study evaluates the efficacy of the IAP inhibitor AT406, alone and with radiation, in both HPV positive (UM-SCC47 and UD-SCC2) and HPV-negative (Cal27 and DET562) HNSCC cell lines...In addition, Liquid Chromatography- Mass Spectrometry (LC-MS/MS) is being utilized to profile changes in protein expression under different treatment conditions to identify molecular contributors to resistance mechanisms. These studies aim to provide mechanistic insights into IAP inhibition and inform the development of combination therapies outcomes in HNSCC."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • BIRC3 • CASP3 • CASP7 • XIAP